Journal

Session

Dr Wan Zaidah Abdullah

 Agenda
Heparin resistance

 BJA, 2002 vol 88, no 4, 467-469

 J A M Anderson and E L Saenko
 Overview
 Heparin was discovered in 1916
 Most widely used anticoagulant but not
all its actions are fully understood
 Eg: pain relief in i.v administration for
the treatment of DVT, how HIT
developed and what is the relevance of
the occurrence of heparin resistance
 Indications
 Prevention of VTE
 Treatment of VTE

 Acute coronary syndrome

 Surgery: cardiac bypass

 Introduction
 Heparin is a negatively charged sulphated
glycosaminoglycan composed of alternating
uronic and glucoronic acid residues
 Commercially prepared are isolated fr porcine
int mucosa or bovine lungs. There are
heterogenous mixtures of polysacharide
chains ranging in molecular weight from 3000
to 30,000.
 Mode of action:
 MOA 1
 1. Antithrombin dependent
 -Activate AT Hep-AT complex

 inactivate thrombin, fXa and

other coagulation factors
 The combination of disaccharide units makes-up
pentasacharide sequence containing high affinity
binding site for AT. This sequence occurs in only
about 1/3 rd of heparin chains and is randomly
distributed
 MOA 2
 2. AT independent
 Direct Inhibition of the intrinsic tenase complex ( PL
complex of FVIIIa, FIXa which generates Fxa)
 * In plasma milieu, AT-dependent effect predominates

 In vivo, variation in response to a fixed dose of

heparin occurs bet individuals
 Pharmacokinetics limitation of heparin caused by the
binding of hep to plasma proteins  Heparin
resistance state
 Significance to
know the ‘R’ state
 1.Prevent over administration of
heparin hemorrhagic consequences
 Particularly during post-op or in the
setting of cardiac bypass surgery and to
consider alternative therapy

 2.In VTE  the phenomenon is of

unclear clinical practice
 Definition of heparin
resistance state
 1. In the context of VTE:
 The need for more than 35,000 u/24 hour to
prolong the APTT into the therapeutic range

 2. Cardiac bypass procedure:

 The definition is based on the ACT with at
least one ACT < 400 secs after heparinization
and/or the need for exogenous antithrombin
administration
 Questions
 1. What causes heparin resistance

 2. Which patient groups are

susceptible?

 Some answers can be gained from the

understanding on the limitation of UFH
 Limitations of
heparin
 1. Biophysical
 Reflects the inability of hep-AT complex
to inactivate FXa bound to platelets
within the prothrombinase, the PL memb
bound fVa – fXa complex,
 in addition to the resistance of fibrin
bound thrombin to inactivation by
heparin
 Limitation of
heparin 2
 2. Pharmacokinetic
 A. Reflects the binding of hep to plasma proteins
including PF4, fib, fVIII and histidine rich
glycoprotein
 As many heparin- binding poteins are acute phaase
proteins/reactants- the phenomenon is often
encountered in acutely ill pts, malignancy, peri or
post partum periods and drugs ( aprotinin and
nitroglycerin – hep clearance)
 B. Lowering of the AT levels by heparin 
contributes to the resistance state
 How to monitor the
anticoagulant effects of
heparin in the lab? … not easy
 1. APTT  failed to prolonged
 APTT has its own limitations:
 Influenced by:
 -blood collection
 -Sampling tube composition
 -Type of anticoagulant
 -Time of sampling to avoid PF4 mediated
neutralization of heparin

 * APTT response to heparin varies

 APTT response to
Heparin
 Possibolityof ApTT lies in the target
range for heparin therapy whilst the
heparin levels is suboptimal occurs in
acquired/congenital factor deficiency,
LA, warfarin effects.
 Monitor
 2. Anti- Xa monitorring
 Less dose of heparin is required compared to when
APTT is used as monitorring agent
 The development of heparin resistance is therefore
an indication for the use of the heparin assay to
measure the anticoagulant effect of the drug
 Chromogenic anti fXa assays have limitations: assay
variation and technique
 Bedside anti fXa monitorring test to permit a quicker
and more accurate asessment of the true
anticoagulant activity of heparin: bypass surgery
 Monitor
 3. ACT

 At present ACT, is the most commonly used

lab test to control heparin effects on
extracorporeal membrane

 ACT results also dependent on the

instrumentation, vary with the presence of
haemodilution and hypothermia
 Heparin Resistance
and CPB
 CPB circuitECM: activate the coagulation pathway
 fXa generation. The inhibition of Fxa in these
situations involves the AT dependent mechanisms of
heparin.
 Imbalance of activation of FX via extrinsic vs intrinsic
p/way

 In general, hep is given 3mg/kg body wt to prevent

extracorporeal clot formation with repeated doses to
maintain ACT > 400 sec to maintain level at 3iu/ml
 Solution to heparin
resistance during CPB
 Potential solution: Argatroban: a selective, reversible
thrombin inhibitor
 Hirudin also a direct thrombin inhibitor : prevent
clotting within the CPB circuit of pts with HIT

 Ecarin clotting time to monitor the antithrombotic

effects (PT activation by the snake venom)
 Pentasacharide: a selective synthetic fXa inhibitors:
once daily subcut dose without monitoring
requirement (prevention of venous thrombosis)
 Conclusion
 Heparin still remains the optimal means of
anticoagulation in CPB, but improvements
are needed in terms of practical bedside
monitorring of its anticoagulant effects.
 Bedside monitorring permit reasessment of
the optimal level of ACT to achieve prior to
starting the bypass circuit
 Significance of
heparin resistance
 In the context of VTE- heparin R has its clinical
relevance?
 What is the outcome of pts treated with empirical
doses of heparin when APTT cannot be
prolonged into the therapeutic range?
 The optimal means of monitorring the
anticoagulant effects in cardiac surgery? to avoid
bleeding post-op and usage of blood products
 Oral heparin in future and synthetic indirect and
direct fXa inhibitors.
Thank you